Bicyclic sulfones and sulfoxides and methods of use thereof

Patent metadata

Field	Value
Publication number	US-12338241-B2
Application number	US-202117340082-A
Country	US
Kind code	B2
Filing date	Jun 6, 2021
Priority date	Oct 31, 2017
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

The invention provides novel compounds having the general formula I:wherein R1, RB1, RB2, n, p, q, the A ring and the B ring are as described herein, pharmaceutical compositions including the compounds, and methods of using the compounds.

First claim

We claim:

1. A method for the treatment of a disease or disorder in a human, the method comprising administration to the human of an effective treatment amount of a compound of, formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 cyanoalkyl, C(O)C 1 -C 6 cycloalkyl-C 1 -C 3 alkyl, C 1 -C 6 Alkyl-N(R 2 ) 2 , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy-C 1 -C 6 alkyl, phenyl, benzyl, difluoro(phenyl)methyl, 4 to 6 membered heteroaryl, 5 to 6 membered heteroaryl, and CH 2 -(5 to 6 membered heteroaryl); wherein
when R 1 is phenyl, benzyl, difluoro(phenyl)methyl, 5 to 6 membered heteroaryl or CH 2 -(5 to 6 membered heteroaryl), the phenyl or heteroaryl moiety of R 1 is optionally substituted by one or two substituents independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, hydroxyl, hydroxymethyl, methoxymethyl, cyano, trifluoromethyl, difluoromethoxy, and trifluoromethoxy, and
when R 1 is cycloalkyl, the cycloalkyl is optionally substituted by by one, two, or three substituents independently selected from the group consisting of fluoro C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxyl, C 1 -C 6 hydroxyalkyl, and cyano;

n is 0, 1 or 2;
each R 2 is independently selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkyl; or two R 2 together with the nitrogen atom to which they are both attached from a 4-6 membered heteroaryl ring;
the A ring and the B together are selected from the group consisting of:

p is 2, and q is 1;
R B1 is independently R 2a and R 2b and each R 2a and R 2b is independently selected from the group consisting of hydrogen, halogen, deutero, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, C 1 -C 6 alkyl-N(R 2 ) 2 , and cyano; and
R B2 is R 4 and R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thioalkyl, C 1 -C 6 alkyl-N(R 2 ) 2 , phenyl benzyl, CH 2 —(C 3 -C 6 cycloalkyl), CH 2 CH 2 —(C 3 -C 6 cycloalkyl), CH 2 -(4 to 6 membered heterocyclyl), CH 2 CH 2 -(4 to 6 membered heterocyclyl), 5 to 6 membered heteroaryl, and CH 2 -(5 to 6 membered heterocyclyl);
wherein when R 4 is phenyl, heteroacyl, or benzyl, the phenyl or heteroacyl ring is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and cyano;

wherein the disease or disorder is selected from the group consisting of Parkinson's Disease, Lewy body dementia, multiple system atrophy, Parkinson-plus syndrome, tauopathies tauopathy, Alzheimer's Disease, frontotemporal dementia, amyotrophic lateral sclerosis, spinal muscular atrophy, primary lateral sclerosis, Huntington's disease, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, muscular dystrophy, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, inherited muscular atrophy, peripheral neuropathies neuropathy, progressive supranuclear palsy, corticobasal degeneration, and demyelinating disease.

2. The method of claim 1 , wherein the disease or disorder is Alzheimer's disease.

3. The method of claim 1 , wherein the disease or disorder is multiple sclerosis.

4. The method of claim 1 , wherein the disease or disorder is Parkinson's disease.

5. The method of claim 1 , wherein the disease or disorder is amyotrophic lateral sclerosis.

6. The method of claim 1 , wherein the disease or disorder is Huntington's disease.

7. The method of claim 1 , wherein the disease or disorder is spinal muscular atrophy.

8. The method of claim 1 , wherein the disease or disorder is ischemia.

9. The method of claim 1 , wherein the A ring and the B ring together are:

10. The method of claim 1 , wherein:
R 3a and R 3b are selected as follows:
one of R 3a and R 3b is H, and the other is selected from the group consisting of hydrogen, deutero, fluoro, chloro, hydroxyl, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cyclopropyl, C 1 -C 4 alkoxy, and C 1 -C 4 haloalkoxy; or
each of R 3a and R 3b is independently selected from the group consisting of deutero, fluoro, chloro, hydroxyl, cyano, and methyl, provided that R 3a and R 3b cannot both be OH or CN; and
R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, and pyridinyl, wherein the phenyl ring or pyridinyl ring is optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, and cyano.

11. The method of claim 1 , wherein R 3a and R 3b are independently hydrogen or fluorine; and R 4 is selected from the group consisting of ethyl, isopropyl n-propyl, trifluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, optionally substituted phenyl, and optionally substituted pyridine-2-yl.

12. The method of claim 1 , wherein the A ring and the B ring together are selected from the group consisting of:

wherein:
R 3a is hydrogen or fluorine;
each R 5 is selected from the group consisting of hydrogen, fluoro, chloro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy; and
m is 1, 2 or 3.

13. The method of claim 1 , wherein the A ring and the B ring together are:

wherein:
each R 5 is selected from the group consisting of hydrogen, fluoro, chloro, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkoxy; and
m is 1, 2 or 3.

14. The method of claim 1 , wherein R 5 is selected from the group consisting of H, F, CI, CH 3 , CH 2 CH 3 , OCH 3 , CF 3 , OCF 3 , CF 2 H, and OCF 2 H.

15. The method of claim 1 , wherein R 5 is halo.

16. The method of claim 1 , wherein the A ring and the B ring together are:

17. The method of claim 1 , wherein R 1 is selected from the group consisting of C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, C 3 -C 6 spirocycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 hydroxyalkyl, phenyl, benzyl, and difluoro (phenyl) methyl.

18. The method of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, tert-butyl, difluoromethyl, trifluoromethyl, cyclopropyl, fluorocyclopropyl, difluorocyclopropyl, phenyl, benzyl, and difluoro (phenyl) methyl.

19. The method of claim 1 , wherein R 1 is selected from the group consisting of ethyl, difluoromethyl, trifluoro

Assignees

• Genentech Inc

Inventors

• Patel Snahel
• Hamilton Gregory
• Stivala Craig
• Chen Huifen
• Daniels Blake

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D249/16

  condensed with carbocyclic rings or ring systems · CPC title

• C07D231/54

  condensed with carbocyclic rings or ring systems · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title